Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.
Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restric...
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2018-02-01
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Series: | PLoS Pathogens |
Online Access: | https://doi.org/10.1371/journal.ppat.1006850 |
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doaj-15b9266be10f461686b0efc0aad703262021-04-21T17:56:39ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-02-01142e100685010.1371/journal.ppat.1006850Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.Ning ZhangMartin ZoltnerKa-Fai LeungPaul ScullionSebastian HutchinsonRicardo C Del PinoIsabel M VincentYong-Kang ZhangYvonne R FreundMichael R K AlleyRobert T JacobsKevin D ReadMichael P BarrettDavid HornMark C FieldRecent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.https://doi.org/10.1371/journal.ppat.1006850 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ning Zhang Martin Zoltner Ka-Fai Leung Paul Scullion Sebastian Hutchinson Ricardo C Del Pino Isabel M Vincent Yong-Kang Zhang Yvonne R Freund Michael R K Alley Robert T Jacobs Kevin D Read Michael P Barrett David Horn Mark C Field |
spellingShingle |
Ning Zhang Martin Zoltner Ka-Fai Leung Paul Scullion Sebastian Hutchinson Ricardo C Del Pino Isabel M Vincent Yong-Kang Zhang Yvonne R Freund Michael R K Alley Robert T Jacobs Kevin D Read Michael P Barrett David Horn Mark C Field Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. PLoS Pathogens |
author_facet |
Ning Zhang Martin Zoltner Ka-Fai Leung Paul Scullion Sebastian Hutchinson Ricardo C Del Pino Isabel M Vincent Yong-Kang Zhang Yvonne R Freund Michael R K Alley Robert T Jacobs Kevin D Read Michael P Barrett David Horn Mark C Field |
author_sort |
Ning Zhang |
title |
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. |
title_short |
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. |
title_full |
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. |
title_fullStr |
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. |
title_full_unstemmed |
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. |
title_sort |
host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2018-02-01 |
description |
Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds. |
url |
https://doi.org/10.1371/journal.ppat.1006850 |
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